REVIEW

Institute for the History of Pharmacy, Philipps-University, Marburg, Germany

Vaccinium myrtillus as an antidiabetic medicinal – research through the ages

A. Helmstädter , N. Schuster

Received December 15, 2009, accepted January 4, 2010 Priv.-Doz. Dr. Axel Helmstädter, Institut für Geschichte der Pharmazie, Roter Graben 10, 35031 Marburg; Govi- Verlag, Carl-Mannich-Str. 26, 65760 Eschborn, Germany [email protected] Dedicated to Prof. Dr. Hartmut Morck, Marburg, on the occasion of his 65th birthday. Pharmazie 65: 315–321 (2010) doi: 10.1691/ph.2010.9402

Bilberry leaves ( myrtillus L.) were one of the most frequently used antidiabetic remedies of plant origin before the discovery of insulin. During the last century, many animal, clinical and phytochemical studies have been undertaken with this plant and its extracts and are summarized here. Overall, it must be concluded that the results were more or less disappointing and could not support the traditional use of leaves against diabetes mellitus which is sometimes recommended even up to the present day.

1. Introduction made of the berries against cough (Bock 1559) and Pietro Andrea Mattioli (1501–1577) believed the juice had a diuretic Prior to the discovery of insulin by Canadian scientists in 1922, and diaphoretic effect (Mattioli 1598), as did Adam Lonitzer medicinal together with highly restrictive diets were (1528–1586) (Lonitzer 1962). Gastrointestinal indications also widely used in the treatment of diabetes mellitus. Although dominate British herbal literature (Sawyer 1903). The early they were of course unable to cure the disease, many of them pharmacopoeias rarely list Vaccinium myrtillus and concentrate had actually shown some hypoglycemic activity and today, sev- on the fruits. For example, the Pharmacopoea Wirtenbergica eral hundred antidiabetic plants are known (Atta-Ur-Rahman (1741) has monographs for Fructus myrtilli and Syrupus myr- and Zaman 1989; Baily and Day 1989). For centuries before tillorum but not for Folia myrtilli. Also Zedler’s encyclopedia the 1920 s, opium was the agent of plant origin most widely reports only the use of berries, which it describes as being used in the treatment of diabetes (Helmstädter 2009), but not usuful against gastrointestinal diseases (Zedler 1735). Dur- for its limited glucose lowering effects, but mainly to “make ing the 19th century, many uses of were reported it easier for the hungry diabetic patient to tolerate his mis- (Kröger 1951b), again as a remedy against various gastroin- ery” (Allan 1972). There are also three medicinal plants which testinal disorders including bacterial infections and parasitoses. are known to have been used quite regularly and significantly Bernstein (1903) focused on the action of bilberries against more often than others in diabetes treatment before the dis- typhoid fever, and initiated the commercial preparation of a liq- covery of insulin: Syzygium cumini, Phaseolus vulgaris and uid extract by the Allan and Hanbury’s company (anon. 1903). Vaccinium myrtillus (Helmstädter 2007). The latter is also one Other indications include skin and mucosal irritations, diseases of the herbal drugs most often recommended against diabetes of the urinary tract, fever and gout. From the end of the 19th cen- by Italian herbalists (Cicero et al. 2004). As there is recent sci- tury, there were reports of the antidiabetic effects of Vaccinium entific interest in antidiabetic plants, summarizing experiences leaf extracts, which were said to have their origin in the folk from folk medicine and older scientific studies might be of value medicine of the Austrian Alps (Mark and Wagner 1925; Allen for guiding future research. As historical knowledge about Syzy- 1927a; Kreitmair 1947; Kleiner 1959), and these soon found gium cumini (Helmstädter 2008) and Phaseolus vulgaris (Carai their way into standard textbooks (Madaus 1938). It has not et al. 2009; Helmstädter 2010) has been reviewed elsewhere, the yet been possible to verify a report referring to “Dr. Richard C. aim of this paper is to summarize investigations of Vaccinium Wagoner of Allentown, NJ” as the discoverer of the antidiabetic myrtillus. action of “” (Davis 1928).

2. Early history of medicinal use 3. Studies prior to the discovery of insulin Vaccinium has been used since at least the Middle Ages, “Heydelbeere” is already mentioned by Hildegard of Bingen Early, but in fact anecdotal, reports of the antidiabetic effects (1098–1179, Kreitmair 1947). The herbals (“Kräuterbücher”) of Vaccinium leaves date from 1892, when a pharmacist from of the Early Modern Period, however, hardly ever mention Colberg near Breslau wrote a short notice about a patient whose Vaccinium myrtillus and if they do, it is for indications other urine sugar content he regularly monitored. After the patient had than diabetes. The use of the fruits (bilberries) was more started to consume two cups of bilberry leaf tea, sugar excre- common than the use of the leaves (Kröger 1951b). Thus tion could no longer be detected. The pharmacist then started Hieronymus Bock (1498–1554) recommended a preparation to prepare and sell bilberry leaf extract (Knorr 1892). One of Pharmazie 65 (2010) 315 REVIEW the first physicians known to be interested in Vaccinium ther- myrtillus was given together with 200 g glucose in 500 mL of apy of diabetes was Rudolf Weil. Initially he achieved positive water. As a result Mark and Wagner observed that the curve of results with a decoction of the herb in one case of diabetes and hyperglycaemia took a lower course compared with that after wished to make this medicine available for more patients in intake of 200 g glucose alone. The absorption of glucose was a preparation with equivalent doses. He cooperated with the apparently not delayed (Mark and Wagner 1925). Studies were pharmacist Max Jasper, owner of a chemical factory in Bernau continued with a preparation called “Myrthillin” on 6 pancrea- near Berlin, who agreed to produce pills later called “Pilulae tectomized dogs. One animal survived for 5 days, another one Myrtilli Jasper” according to Weil’s suggestions, including the for 29 days. In dog 1 the preparation reduced blood glucose by use of young leaves harvested before the fruits appear (Weil about 45% and in dog 10 by about 50%; in this case glucosuria 1892). Each pill contained 0.12 g extractum foliorum myrtillo- was stopped. According to the authors the extract could keep a rum. Weil tested these pills in some of his patients and presented depancreatized dog alive as long as it was given. The effect on the results of 3 cases. After intake of 3 to 15 pills, e.g. 0.36 to blood glucose was described as being dependent on the method 1.8 g extract, urine glucose vanished completely or almost com- of application (Eppinger et al. 1925). pletely within 12 weeks. The patients were described as having In the US, Frederick Madison Allen (1876–1964, for life and improved health status and gaining body weight. Weil stated that work see Medvei 1993) from Morristown, NJ, tried an extract these results were similar to those of some of his colleagues. He of Vaccinium myrtillus called myrtillin in fully and partially added that all his patients had to keep strictly to a special diet depancreatized dogs and in patients. A daily dose of 1 g of an which was low in carbohydrates and rich in vegetables. The alcoholic extract (for preparation see Allen 1927a), was given at physician recommended this diet for every patient who wanted least one hour before mealtime. Allen found that the preparation to take Pilulae Myrtili Jasper. could considerably prolong the survival time of fully depancre- In 1902, Bruno Steffan from Wädensweil tested the effect of atized dogs and that it tended to stabilize blood sugar. In partially Pilulae Myrtilli Jasper along with many other preparations rec- depancreatized dogs the extract kept the dogs in good condition ommended against diabetes on himself. In his first test Steffan with sugar-free urine and normal blood glucose. Clinical tri- took 16 pills within 12 hours which meant a total dose of 1.92 g als with 81 patients (in fact only 60 patients after Allen had aqueous extract. Three hours after an intake of 50 g glucose excluded 21, mainly for “insufficient length of observation”) his urine glucose decreased by about 30% and his urine volume showed that the extract was not a reliable remedy as it failed in was reduced by about 5% over the following 24 h compared with 24 cases. In 36 cases there was some benefit, which led to an an intake of glucose only. In a second trial he took 36 pills in insulin dose reduction ranging from 6 to 28 units. In 6 patients 4 days, which meant a total dose of 4.32 g extract. This time urine insulin therapy could be entirely stopped. In Allen’s tests the glucose in the first 3 h after an intake of glucose was reduced therapy achieved best results in the mildest cases, poorest in by about 40% and urine volume decreased by about 12%. The children and best in the middle aged or elderly. Even the largest author concluded that Pilulae Myrtilli Jasper had a noticeable doses of 20 grams per day proved in Allen’s experiments to be although not very strong effect on glucose excretion (Steffan nontoxic. He claimed a “possible vitamin nature” of the sub- 1902). stance isolated (Allen 1927a, b). Eventually, Allen lost a lot In 1908, the German doctor Martin Kaufmann from Mannheim of money in the development of a myrtillin preparation which studied a variety of antidiabetic remedies including Vaccinium ended up in severe personal disappointment (Medvei 1993). myrtillus administered as a tea and formulated in Pilulae The same year, Leonard Benjamin Shpiner from the Univer- Myrtilli Jasper. He observed two patients who were on a spe- sity of Chicago repeated and extended Allen’s studies. He used cial diet. First he gave a daily amount of 800 mL tea to a an extract of Vaccinium myrtillus named myrtillin which was 50 year old man. The man took the tea for 7 to 30 days consec- not further characterised for experiments in dogs which were utively with a break of one week. Kaufmann observed a slight partially or totally pancreatectomised. Some of the dogs were but practically irrelevant reduction in urine glucose levels. Sev- tested during experimental hyperthyroidism. Three to 6 tablets eral weeks later this patient received 6 Pilulae Myrtilli Jasper á 5 grain of the supposedly active agent were given daily to dogs daily for one week. Again, Kaufmann did not see a clear effect on a standard diet. The intake of the preparation resulted in a of the pills and described the therapy as harmless but useless reduction of the hyperglycaemia and urine sugar in the totally (Kaufmann 1908). A 45 year old patient got the same tea as in depancreatized dogs, so that these animals survived longer. In test one on 6 consecutive days. In his case also no effect of the partially depancreatized dogs relying on only 1/20 of the organ tea was noticeable. no diabetes symptoms developed. Here no glycosuria appeared and normal blood sugar levels were noted during experimental hyperthyroidism (Shpiner 1928). Blair Holcomb (born 1894) from Portland, Oregon, also referred 4. Studies after the discovery of insulin to Allen when he tested a preparation which he called myrtomel. It is interesting to note that after insulin had been made available, He tested it in 18 patients aged 6 to 64 of whom 4 patients stopped scientific interest in antidiabetic plants did not disappear but even taking it. Eight patients were described as “severe” cases by grew significantly. Most probably, this is due to the fact that the the author and 12 were on insulin. According to Holcomb his insulin discoverers themselves were convinced of the presence remedy led to a reduction of insulin dose in 7 of 12 patients and of an “insulin-like” substance in lower organisms and plants. In 2 patients could completely stop insulin injections. He described particular James Bertram Collip (1892–1965) believed in such the action of the active sugar lowering principle as being slower “plant hormones” called “glukokinin” in a publication edited in patients without insulin than in patients taking both insulin just one year after the discovery of insulin (Collip 1923). The and his preparation (Holcomb 1928). idea of “vegetable insulinoids” (Labbé 1936) initially triggered E. M. Watsonfrom the Department of Medicine of the University a large amount of research including investigations on bilberry of Western Ontario in London treated patients with tablets con- leaves. taining 0.3 g of Vaccinium myrtillus extract each. His study Robert E. Mark and R. J. Wagner from the physiological depart- group consisted of 16 people, 3 of them being children aged ment of the University of Vienna carried out several studies with 16 and 12. Four patients were described as “severe” cases and Vaccinium preparations. In 1925 they tried a remedy made of the 13 were on insulin. The tablets were given one hour before a herb in 12 healthy dogs. Aqueous extract from 10 g Vaccinium meal. Watson said that the intake of tablets reduced the doses of 316 Pharmazie 65 (2010) REVIEW insulin in 6 cases and also reduced the blood glucose level. In In mice made diabetic with alloxan, a reduction in blood glu- 7 cases the tablets increased carbohydrate tolerance. According cose levels by about 10% was reported in the early 1990s, but to the author the best results were obtained in the milder cases unfortunately, these experiments are not documented in detail and in middle-aged or elderly patients whereas the effects of (Hänsel et al. 1996). the remedy were lost in the presence of even a slight infection Cignarella et al. (1996) tested a dried hydroalcoholic extract of (Watson 1928). Vaccinium myrtillus in streptozotocin-diabetic rats (3.0 g extract Elmer Louis Sevringhaus (born 1894), a famous endocrinologist per kg body weight). The plasma glucose levels dropped by from the Department of Medicine of the University of Wisconsin about 26% within three weeks of treatment, an effect con- (Madison) discussed the effect of two antidiabetic preparations: sidered as “statistically, though not biologically significant”. synthalin and myrtomel. The preparation of Vaccinium myrtillus The authors also report a significant fall in triglyceride levels made by the Squibb Research Laboratory was described as being and therefore found that the traditional plant treatment “could less promising than synthalin, a guanidine derivative (Sevring- deserve attention for its activity on certain lipid metabolism haus 1928, see also Wilder and Allan 1928). However, details disorders.” about the studies with myrtomel are not reported. Petlevski et al. (2001) tested a multiingredient preparation com- The French scientists M. F. Rathery and L. Levina tried an alco- posed of Myrtilli folium and nine other plant extracts, patented holic preparation of fresh Vaccinium myrtillus leaves in normal as an antidiabetic remedy in Croatia. In alloxan-induced non- and depancreatized dogs as well as in six human diabetics. In obese diabetic mice, they found a decrease in blood glucose and three of the patients the preparation reduced blood glucose and fructosamine levels. in two patients a reduction of blood glucose was observed after Vaccinium was also included in screening programs aimed at doubling the dose. In two patients urine glucose vanished. The identifying alpha-amylase inhibitors and activators of the human scientists remarked that no immediate effect was to be expected, peroxisome proliferator-activated receptor gamma and results but nevertheless there was undoubtedly an effect of some kind indicated that bilberry leaf extracts have some activity in both (Rathery and Levina 1928). models (Melzig and Funke 2007; Rau et al. 2006). From that Braun and Rees (1935) treated hyperglycemia induced in normal point of view, some antidiabetic activity seems possible. fasting rabbits by giving 10 g glucose per kg body weight with 1 g/kg myrtillin, defined as “the hypoglycemic fraction of an alcoholic hydrochloric acid extract of the dried green leaves of 6. The search for an active principle the whortleberry or the ”. They found some effect, but stated that the hyperglycemia was “depressed distinctly but very Along with the studies of the antidiabetic activity of Vaccinium variably”. extracts the search for an active principle went on. This was In a Ph.D. thesis published in 1936, a Vaccinium containing dominated by Allen’s proposal of a compound named “myr- combination product, Norisdiabet, was tested (Pomp 1936). In tillin” which was said to be present not only in Vaccinium but addition to bilberry leave extract, the preparation contained in all green plants, yeasts and bacteria. It was said to have been a variety of salts derived from Spa waters, alkalizing agents obtained twice “in traces from dog livers” (Allen 1927a) and like sodium hydrogen carbonate und Syzygium cumini extract. seems to represent the “glukokinin” initially suggested by Col- ‘Norisdiabet”, which was marketed by a pharmacy in Nurem- lip. Allen (1927a) gave a detailed description of its preparation berg, Germany, was tested in 7 patients without any benefit. by extraction with acidified alcohol (50%). After removal of In 1938 the pharmacologist Hans Dietering from Berlin tested proteins by addition of alcohol (95%) an aqueous solution of a daily oral dose of 0.15 to 18 g/kg body weight of an aque- ammonium sulphate (20%) is added which yields a “flocculent ous extract in more than 50 cats and rabbits. The extracts precipiate” containing myrtillin. It is said to be “a greyish or were commercially produced by the pharmaceutical company brownish amorphous substance, not chemically pure” (Allen Krause-Medico according to their “dispert” procedure. The ani- 1927a, for the preparation method see also Merck 1925). The mals received up to 1.5 g bilberry leaf extract per kg body weight. supernatant should contain the “sugar-raising principle” which Referring to Weil (1892) he tested extracts from young leaves was also suggested to be present in Vaccinium leaves. and those derived from older ones, both in different doses. How- In principle, this definition of “myrtillin” was also given by ever, he could not find a reduction in blood glucose with any Braun and Rees (1935) and still accepted by Kreitmair (1947). of these preparations and called the preparation therapeutically He points out that myrtillin (or myrthillin) is glucosidic in useless. He even feared toxicity due to the reported hydro- nature and must not be confused with the anthocyane dye quinone content of the leaves (Dietering 1938). Oettel (1936) extracted from bilberries and already named myrtillin by Will- had already pointed out that Vaccinium species might be toxic stätter and Zollinger (1915). Avoiding confusion might have due to their high contents of hydroquinone, a substance which been the reason why the antidiabetic principle was later called was said to elevate blood glucose levels and to interact with urine “myrtomel” (Holcomb 1928; Jorgensen and Lynn 1935). In the glucose determination methods. However, today it is doubted if 1930s Edgars (1934) and Galimard (1939) proposed a methoxy Vaccinium myrtillus contains hydroquinone in relevant concen- galloyl glucoside “neomyrtillin” as a chemical entity with the trations at all (Hänsel et al. 1996). As early as 1929, Shpiner molecular formula C24H36O18. In contrast, Edgars described suggested that commercial blueberry leave extracts are “non- Allen’s extract as “a group of active principles which have toxic to [...] dogs when administered orally in what may be been roughly grouped under the pseudonym of myrtillin”. He considered excessive doses” (i.e., up to 3.9 g extract which was is highly enthusiastic about the therapeutic use of neomyr- said to be “two to four times the dosage necessary for its thera- tillin, whose existence, however, could not be verified in the peutic effect in man”; Shpiner 1929). extensive investigations done by Kröger (1951a). Quite surpris- ingly, Hänsel et al. (1996) are still convinced of the “glukokinin neomyrtillin” in the aerial parts of the plant and suggest it to be a methoxylated glycoside of gallic acid. Hydroquinone (Oettel 5. Studies after World War II 1936; Kreitmair 1947) and arbutin (Kröger 1951a) are no longer In contrast to other antidiabetic plants known from traditional regarded as being contained in considerable amounts. Accord- medicine, Vaccinium myrtillus was only rarely investigated after ing to Zareba et al. (2005), anthocyanidins are responsible for World War II. the proposed “long-term hypoglycemic effect” of extracts from Pharmazie 65 (2010) 317 REVIEW Even the largest doses (20non g/day) toxic “possible vitamin nature” of myrtillin no effect on ratsrabbits and 21/81 patients excluded from study on way of application Increase in body weight Improved health status unknown) who could not find any effect with PMJ. No unpleasant events ocurred No clear definition of theextract type used of 1) reduces or removes urine glucose 2) keeps the Minkowski-quotient small 3) keeps alive a depancreatized dog as long as Mt is given Mt a harmless therapy without any therapeutic effect Good results, comparable to those of “colleagues.” Should be used in combination with diet In 36/60 cases some benefit,reduction insulin –6–28 units 6/60 patients could stop insulin therapy Considerably prolongs survival time of depancreatized dogs Dog 1: Mt reduced blood357 glucose mg-% from to 192 mg-% Dog 10: reduction in bloodfrom glucose 416 mg-% to 211glucosuria mg-%, stopped - ca. 40% Urine volume - ca. 12% Patient 1: on 800 ccmobservation: tea, slight, first practically irrelevant reduction in urine glucose levels Lower curve of the coursehyperglycaemia of -ca. 30% Urine volume in 24 h - ca. 5% Patient 2: 800 ccm teaPatient showed 1: no second effect observation: noeffect clear of the PMJ Urine glucose completely vanished within 12 weeks 2 years 800 ccm tea of MtPMJ or per 6 day 4.32 g aE (36 PMJ) in 4 d Urine glucose (3h) 500 ccm aE (10 gmyrt.) Vacc. with 200 g glucose daily 1.92 g aE (16 PMJ) in 12 h Urine glucose (3 h) Small effect on glucose excretion Refers to Kétly (details extracts as an antidiabetic agent 81 Patients In 24/60 human cases Mt failed 2. 45 years of age Both patients got a special diet 12 healthy dogs after intake200 of g glucose 6 dogs without pancreas Mt 2 dogs survived 5 and 29 days Mt Effect on blood glucose depends glucose intake Vaccinium (1925) (1925) Allen (1927) Dogs 1 g eE (Mt) daily for up to Kaufmann (1908) 2 patients: 1. 50 years of age Mark and Wagner Eppinger et al. Table: Studies with Author (year)Weil (1892) Patients/animals 3 Patients Vacc. prep. and dose 0.36–1.8 g aE (3–15 PMJ) Results Author’s conclusions Remarks Steffan (1902) 1 healthy volunteer after 50 g

318 Pharmazie 65 (2010) REVIEW References to Allen Effects of remedy were lostthe in presence of even ainfection slight Case reports on the usemyrtomel of not presented Diarrhoea was observed as side effect In high doses toxic duehydroquinone to content Mt may prove potentially useful for treatment of dyslipidaemia associated with impaired TG-rich lipoprotein clearance Action of Mm in patientsinsulin without somewhat slower than in patients taking insulin and myrtomel together Best results obtained in the milder cases and in middle-aged or elderly patients myrtomel No immediate effect but aeffect certain after prolonged use No success in animal studies Reduction of insulin dose inpatients, 7/12 stopping of insulin intake2/12 in patients Reduction of insulin dose inreduction 6 in cases blood and glucose levels,cases in increased 7 carbohydrate tolerance - Mt reduces the hyperglycemiaglucosuria and in the totally pancreatectomized dogs, longer survival - no diabetes developed inpancreatectomized partially dogs (1/20 left) - urine sugar free andnormal blood level sugar when on Mt ispartially given pancreatectomized to (loss of 7/8) dogs during experimental hyperthyroidism and in 2 patients aftervanishing dose of doubling, urine glucose No reduction in blood (!) glucose levels Therapeutically not useful Plasma glucose levels dropped by26% about at two different stages of diabetes Preparation called “myrtomel” given 1–9 months Tablets of 0,3 gE Mm given one hour before a meal 3–6 tablets of Mt (5per grain tablet) were given daily to dogs on astandard daily diet eE0.15–18 g/kg b.w. aE (“Dispert” preparation) extract of the leaf In 3 patients reduction of blood glucose and 12, 13 adults, aged“severe” 23–77), cases, 4 13 under insulin Patients Synthalin, Mm Synthalin more promising than adults) 8 “severe” cases, 12 under insulin Normal and pancreatectomized dogs, 6 patients 1. 2 totally pancreatectomized 2. partially pancreatectomized (loss of 19/20) 3. partially pancreatectomized (loss of 7/8) dogs during experimental hyperthyroidism ) Continued (1928) (1928) Rathery / Levina Watson (1928) 16Severinghaus Patients (3 children, aged 16 Shpiner (1928) Dogs: Dietering (1938) More than 50 cats and rabbitsCignarella (1996) Daily oral Streptozotocin-diabetic doses rats of A dried hydroalcoholic Table: ( Author (year)Holcomb (1928) 18 Patients (6 Patients/animals children, 12 Vacc. prep. and dose Results Author’s conclusionsaE: aqueous extract; eE: ethanolic extract; Mt: myrt(h)illin; Mm: myrtomel; PMJ: Pilulae Myrtilli Jasper Remarks

Pharmazie 65 (2010) 319 REVIEW the berries (!). Today’s research concentrates on the effects of Edgar NK (1934) The blueberry. The pharmacology of neomyrtillin from anthocyanidins present in the plant (Morazzoni and Bombardelli blueberry leaf with a description of vaccinium caeserense. Complete anal- 1996). yses of leaf and fruit. The Gaw Printing Company, Pub, Jersey City. (Ph.D. thesis 1929). Eppinger H, Mark E, Wagner RJ (1925) Weitere Beobachtungen über die Wirkung von aus Heidelbeerblättern hergestellten Präparaten (Myrthillin) 7. Conclusion auf pankreaslose Hunde. Klin Wschr 4: 1870–1871. From the perspective of the early 20th century, Vaccinium myr- Frohne D (2002) Heilpflanzenlexikon. 7th ed. Stuttgart, pp. 556– tillus was among the most promising antidiabetic medicinal 557. Galimard J (1939) Les Vacciniées et, en particulier, le Vaccinium Myrtillus plants, as it was one of the most often used hypoglycemic agents L. en thérapeutique. Ph.D. thesis, Paris. of that era. It was intensively studied in the 1920’s when Col- Hänsel R, Keller K, Rimpler H, Schneider G (eds.) (1996) Drogen P-Z. lip’s glykokinin hypothesis strongly stimulated the search for Hager’s Handbuch der Pharmazeutischen Praxis, 5th ed., vol. 6, pp.1051– plant ingredients with antidiabetic activity. However, results 1067. were inconsistent and serious toxicity was discussed. High qual- Helmstädter A (2007) Antidiabetic drugs used in Europe prior to the dis- ity studies from recent times are rare and do not support the use of covery of insulin. Pharmazie 62: 717–720. Vaccinium as an antidiabetic agent. However, some activity may Helmstädter A (2008) Syzygium cumini (L.) Skeels (Myrtaceae) against diabetes–125 years of research. Pharmazie 63: 91–101. be explained by the ability of extracts to inhibit alpha-amylase Helmstädter A (2009) Arzneimittelgeschichte: Antidiabetika vor Entdeck- and to (weakly) activate the human peroxisome proliferator- ung des Insulins. Pharm Ztg 154: 3921–3926. activated receptor (PPAR) gamma. Nevertheless, in view of Helmstädter A (2010) Beans and diabetes–Phaseolus vulgaris prepa- toxicological risks, the use of bilberry leaf preparations is not rations as antihyperglycemic agents. J Med Food, in print. (doi: recommended by the German Commission E monographs and 10.1089/jmf.2009.0002). in standard textbooks (Frohne 2002). There seems still to be Holcomb B (1928) Myrtomel in diabetes mellitus, the results of its use. some confusion about the active ingredients of the plant. Northwest Med 27: 586–588. It is well known that screening historical knowledge can lead to Jorgensen PS, Lynn EV (1935) Vegetable extracts and blood sugar. J Am Pharm Assoc 24: 389–392. important information for today’s research (Riddle 2002; Buenz Kaufmann M (1908) Ueber die Einwirkung von Medikamenten auf et al. 2004). In the case of Vaccinium myrtillus, however, his- die Glykosurie der Diabetiker. 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